Home Protein ExpressionMAPKKKs

MAPKKKs

Mitogen-activated protein kinase (MAPK) signaling pathways mediate cellular responses to many stimuli including growth factors, hormones, cytokines and environmental stresses. MAPK pathways can be divided into those that predominantly respond to mitogens and those that predominantly respond to stress. The extracellular signal regulated kinase (ERK1 and ERK2) pathways are activated by mitogens and play an important role in controlling cell growth and differentiation. The stress-activated MAPK pathways include the c-Jun N-terminal kinase (JNK) and p38 pathways that are implicated in apoptosis and the immune response. The ERK5 MAPK pathway responds to both growth signals and certain stresses. All MAPK pathways feature a three-kinase cascade whereby MAPKs are activated by phosphorylation by a MAPK kinase (MKK or MEK) and MKKs are activated by serine/threonine phosphorylation by MAPK kinase kinases (MAPKKK or MAP3K).

The MAP3K group consists of a large diverse group of protein kinases with overlapping specificities for MKKs. They include members of the RAF, MEKK (MEK kinase), MLK (mixed lineage kinase), and TAO (thousand and one amino acid) families and the protein kinases MOS, ASK1 (apoptosis signal-regulating kinase-1), TAK1 (TGFβ-activated kinase-1) and TPL2 (tumor progression locus-2). The activities of MAP3Ks can be regulated by a number of mechanisms including phosphorylation, interaction with small GTPases, proteolysis, and binding to regulatory or scaffold proteins.

The RAF family are components of ERK signaling pathways and phosphorylate the highly related MEK1 and MEK2. RAF proteins are activated by their recruitment to Ras GTPase at membranes and by phosphorylation at regulatory sites. Mutations in RAF, particularly B-RAF, are associated with human cancers. A second MAP3K that is specific for the ERK pathway is MOS which is primarily expressed in germline cells and is implicated in oocyte maturation. The TPL2 MAP3K activates the ERK pathway and plays an important role in the innate immune response.

The MEKK and MLK families of MAP3Ks and the less well characterized TAO family are components of stress-activated MAPK pathways. The MEKK and MLK families can be activated by Rho-family GTPases and STE20-like protein kinases. MEKK1 can also be activated by proteolysis following apoptotic stimuli. Caspases cleave MEKK1 to release the catalytically active C-terminus that is highly pro-apoptotic. While predominantly involved in stress-signaling some members of these families can function as regulators of ERK pathways. For example, MEKK2 and MEKK3 are components of the ERK5 cascade, MEKK1 can function as a ubiquitin ligase and cause degradation of ERK1/2, and MLK3 has been suggested to be required for B-RAF signaling to ERK1/2.

Additional MAP3Ks that are components of JNK and p38 signaling pathways include ASK1 and TAK1. These MAP3Ks have distinct mechanisms of activation. ASK1 mediates apoptosis induced by oxidative stress and is activated by dissociation from a redox-sensitive inhibitory protein, thioredoxin. TAK1 is activated by TGFβ and cytokines via a mechanism dependent on the ubiquitination of an associated protein, TRAF6.

In addition to their central roles in MAPK signaling some MAP3Ks are components of other signaling pathways. For example C-RAF, MEKKs and TAK1 can activate the NF-kB signaling pathway independently of MAPKs. Also, a MAP3K related kinase NIK (NF-kB inducing kinase) is a component of NF-kB signalling pathways but has no reported role in MAPK signalling.

The large body of literature on MAPK pathways suggests that there is a high level of promiscuity at the level of MAP3Ks. However it is clear from gene-deletion studies in mice and lower eukaryotes that individual MAP3Ks have distinct cellular roles. One important regulatory mechanism for achieving specificity is by scaffold proteins linking particular MAP3Ks to particular MAPK modules in response to a stimulus.

The Table below contains accepted modulators and additional information. For a list of additional products, see the "Similar Products" section below.

Family Members	RAF	MOS	MEKK	MLK
Other Names	Proto-oncogene serine-threonine protein kinase	Proto-oncogene serine-threonine protein kinase	Mitogen-activated protein kinase kinase kinase MAP3K	Mitogen lineage kinase
Molecular Weight (kDa)	67 – 85 kDa	39 kDa	69 – 182 kDa	91 – 122 kDa
Isoforms	A-RAF B-RAF C-RAF (RAF1)	Not Known	MEKK1 (M6939) (MAP3K1) MEKK2 (MAP3K2) MEKK3 (MAP3K3) MEKK4 (MTK1, MAP3K4)	MLK1 (MAP3K9) MLK2 (MST, MAP3K10) MLK3 (SPRK, PTK1, MAP3K11) MLK4 MLK7 (ZAK, MRK, MLTK) DLK (MUK, ZPK, MAP3K12) LZK (MAP3K13)
Species	Vertebrate Fly Worm	Vertebrate Fly	Vertebrate Fly Worm Yeast	Vertebrate Fly Worm
Domain Organization	Ser/Thr-protein kinase domain Cys-rich domain Ubiquitin-like domain Ras-binding domain	Ser/Thr-protein kinase domain	Ser/Thr-protein kinase domain Ring-ZF domain Ras-binding domain MEKK1 PH-domain (MEKK1, MEKK4) CRIB (MEKK4)	Ser/Thr-protein kinase domain Leucine-zippers domain SH3 domain CRIB domain (MLK1-4) SAM domain (MLK7)
Phosphorylation Sites	Ser²¹⁴ Ser²⁹⁹ Tyr³⁰² Thr⁴⁵² Thr⁴⁵⁵ Ser⁵⁸² (A-RAF) Ser³⁶⁴ Ser⁴⁴⁵ Thr⁵⁹⁸ Ser⁶⁰¹ Ser⁷²⁸ (B-RAF) Ser⁴³ Ser²³³ Ser²⁵⁹ Ser³³⁸ Tyr³⁴¹ Thr⁴⁹¹ Ser⁴⁹⁴ Ser⁶²¹ (C-RAF)	Ser³	Thr¹³⁸³ Thr¹³⁹⁵ (MEKK1) Thr⁵²³ (MEKK2) Thr⁵³⁰ (MEKK3) Thr¹⁵⁰⁴ (MEKK4)	Thr²⁷⁷ Ser²⁸¹ + 11 C-terminal sites (MLK3)
Tissue Distribution	Ubiquitous	Germ cells	Ubiquitous	Ubiquitous
Binding Partners/ Associated Proteins	KSR1, 2 RKIP CNK BAG1 SUR8 Paxillin 14-3-3	Not Known	LAD OSM (O1637, O9635) JLP Mip1 (M6167, M6292, M6542, M6417) GADD45 JSAP1 TRAFs 14-3-3 JNKBP1	JIP1 JIP2 JIP3 MBIP POSH 14-3-3
Upstream Activators	RAS (R9894) RAP1 (R2152) PAK	CDC2-cyclin B	RAS RAC1 HPK1 CDC42 GCK RIP	RAC1 CDC42 HPK1 PAK
Downstream Activation	MEK1 MEK2	MEK1 MEK2 Myt1 MyoD	MEK1 MEK2 MKK3 MKK4 MKK5 MKK6 (M5814) MKK7 IKK	MKK3 MKK4 MKK6 (M5814) MKK7
Activators	Growth factors	Progesterone (P0130, P3972) Growth factors	Stress Cytokines Growth factors	Stress Cytokines Growth factors
Inhibitors	BAY-43-9006	Not Known	Not Known	CEP-1347
Selective Activators	Not Known	Not Known	Not Known	Not Known
Physiological Function	Cell growth	Oocyte maturation	Stress responses Development	Stress responses Development Neuronal apoptosis
Disease Relevance	Cancer (B-RAF)	Not Known	Not Known	Not Known

Family Members	TAO	ASK	TAK1	TPL-2
Other Names	PSK JIK KFC	Not Known	MAP3K7	COT MAP3K8
Molecular Weight (kDa)	105 – 138 kDa	112 – 155 kDa	67 kDa	58 kDa
Isoforms	TAO1 (PSK2, KFC-B, MARRK) TAO2 (PSK1, KFC-C) TAO3 (JIK, KFC-A)	ASK1 (MAPKKK5, MAP3K5) ASK2 (MAPKKK6, MAP3K6)	Not Known	Not Known
Species	Vertebrate Fly Worm	Vertebrate Fly Worm	Vertebrate Fly Worm	Vertebrate
Domain Organization	Ser/Thr-protein kinase domain	Ser/Thr-protein kinase domain	Ser/Thr-protein kinase	Ser/Thr-protein kinase
Phosphorylation Sites	Not Known	Ser⁸³ Thr⁸³⁸ (ASK1)	Thr¹⁸⁷ Ser¹⁹²	Thr²⁹⁰ Ser⁴⁰⁰
Tissue Distribution	Ubiquitous	Ubiquitous	Ubiquitous	Ubiquitous
Subcellular Localization	Cytosol	Cytosol	Cytosol	Cytosol
Binding Partners/ Associated Proteins	Tubulin	β-Arrestin-2 TRAF2 CDC25A Thioredoxin (T0910, T3658) AIP1 SKRP1 Daxx Nef 14-3-3 JIP3	TAB1, 2, 3 SMAD3 TRAF6 SEF RKIPTAB1, 2, 3 SMAD3 TRAF6 SEF RKIP	NF-kB1/p105 AKT (A8729, A9104) KSR2 ABIN-2 TRAF2
Upstream Activators	Not Known	CaMKII IRE1	K63-polyubiquitination	Not Known
Downstream Activation	MKK3 MKK4 MKK6 (M5814) MKK7	MKK3 MKK4 MKK6 (M5814) MKK7	MKK3 MKK4 MKK6 (M5814) IKK HIPK2	MEK1 MEK2 MKK4 MKK5 MKK6 (M5814) NIK
Activators	Carbachol Osmotic stress	Stress Calcium GPCR	Stress Cytokines Wnt TGF-β	Cytokines LPS (L2630)
Inhibitors	Not Known	Not Known	Not Known	Not Known
Selective Activators	Not Known	Not Known	Not Known	Not Known
Physiological Function	Stress responses	Stress responses Neuronal apoptosis Heart function	Stress responses	Inflammation response
Disease Relevance	Not Known	Not Known	Not Known	T-cell lymphoma

References

Chadee DN, Kyriakis JM. 2004. MLK3 is required for mitogen activation of B-Raf, ERK and cell proliferation. Nat Cell Biol. 6(8):770-776. https://doi.org/10.1038/ncb1152

Chen Z, Cobb MH. 2001. Regulation of Stress-responsive Mitogen-activated Protein (MAP) Kinase Pathways by TAO2. J. Biol. Chem.. 276(19):16070-16075. https://doi.org/10.1074/jbc.m100681200

Craig EA, Stevens MV, Vaillancourt RR, Camenisch TD. 2008. MAP3Ks as central regulators of cell fate during development. Dev. Dyn.. 237(11):3102-3114. https://doi.org/10.1002/dvdy.21750

Gallo KA, Johnson GL. 2002. Mixed-lineage kinase control of JNK and p38 MAPK pathways. Nat Rev Mol Cell Biol. 3(9):663-672. https://doi.org/10.1038/nrm906

Hagemann C, Blank JL. 2001. The ups and downs of MEK kinase interactions. Cellular Signalling. 13(12):863-875. https://doi.org/10.1016/s0898-6568(01)00220-0

Kostenko S, Shiryaev A, Dumitriu G, Gerits N, Moens U. 2011. Cross-talk between protein kinase A and the MAPK-activated protein kinases RSK1 and MK5. Journal of Receptors and Signal Transduction. 31(1):1-9. https://doi.org/10.3109/10799893.2010.515593

Kyriakis JM, Avruch J. 2001. Mammalian Mitogen-Activated Protein Kinase Signal Transduction Pathways Activated by Stress and Inflammation. Physiological Reviews. 81(2):807-869. https://doi.org/10.1152/physrev.2001.81.2.807

Lu Z, Xu S, Joazeiro C, Cobb MH, Hunter T. 2002. The PHD Domain of MEKK1 Acts as an E3 Ubiquitin Ligase and Mediates Ubiquitination and Degradation of ERK1/2. Molecular Cell. 9(5):945-956. https://doi.org/10.1016/s1097-2765(02)00519-1

Morrison DK, Davis RJ. 2003. Regulation of MAP Kinase Signaling Modules by Scaffold Proteins in Mammals. Annu. Rev. Cell Dev. Biol.. 19(1):91-118. https://doi.org/10.1146/annurev.cellbio.19.111401.091942

10.

O'Neill E, Kolch W. 2004. Conferring specificity on the ubiquitous Raf/MEK signalling pathway. Br J Cancer. 90(2):283-288. https://doi.org/10.1038/sj.bjc.6601488

11.

Saito H. 2010. Regulation of cross-talk in yeast MAPK signaling pathways. Current Opinion in Microbiology. 13(6):677-683. https://doi.org/10.1016/j.mib.2010.09.001

12.

Sekine Y, Takeda K, Ichijo H. 2006. The ASK1-MAP Kinase Signaling in ER Stress and Neurodegenerative Diseases. CMM. 6(1):87-97. https://doi.org/10.2174/156652406775574541

13.

Takeda K, Matsuzawa A, Nishitoh H, Ichijo H. 2003. Roles of MAPKKK ASK1 in Stress-Induced Cell Death. Cell Struct. Funct.. 28(1):23-29. https://doi.org/10.1247/csf.28.23

14.

Tunquist BJ. 2003. Under arrest: cytostatic factor (CSF)-mediated metaphase arrest in vertebrate eggs. 17(6):683-710. https://doi.org/10.1101/gad.1071303

15.

Wang C, Deng L, Hong M, Akkaraju GR, Inoue J, Chen ZJ. 2001. TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature. 412(6844):346-351. https://doi.org/10.1038/35085597

16.

Wellbrock C, Karasarides M, Marais R. 2004. The RAF proteins take centre stage. Nat Rev Mol Cell Biol. 5(11):875-885. https://doi.org/10.1038/nrm1498

Sign In To Continue

To continue reading please sign in or create an account.

Don't Have An Account?